96929-05-4|Ethyl 2-(((tert-butoxycarbonyl)amino)methyl)thiazole-4-carboxylate| Ambeed

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Quality Control of [ 96929-05-4 ] Purity: 98% SDS Specification

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Product Details of [ 96929-05-4 ]

CAS No. :	96929-05-4
Formula :	C₁₂H₁₈N₂O₄S
M.W :	286.35
SMILES Code :	O=C(C1=CSC(CNC(OC(C)(C)C)=O)=N1)OCC
MDL No. :	MFCD09878704
InChI Key :	IIBLNWWFRAOZDR-UHFFFAOYSA-N
Pubchem ID :	9925901

Safety of [ 96929-05-4 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H332-H335
Precautionary Statements:	P261-P280-P305+P351+P338

Computational Chemistry of [ 96929-05-4 ] Show Less

Physicochemical Properties

Num. heavy atoms	19
Num. arom. heavy atoms	5
Fraction Csp3	0.58
Num. rotatable bonds	8
Num. H-bond acceptors	5.0
Num. H-bond donors	1.0
Molar Refractivity	71.72
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	105.76 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	3.33
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	2.04
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.19
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	0.54
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	2.56
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.13

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.57
Solubility	0.776 mg/ml ; 0.00271 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-3.89
Solubility	0.037 mg/ml ; 0.000129 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-3.13
Solubility	0.214 mg/ml ; 0.000746 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	No
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	No
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	Yes
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-6.6 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	0.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	1.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<1.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	3.35

Application In Synthesis of [ 96929-05-4 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Downstream synthetic route of [ 96929-05-4 ]

[ 96929-05-4 ] Synthesis Path-Downstream 1~35

1
[ 70-23-5 ]
[ 89226-13-1 ]
[ 96929-05-4 ]

Yield	Reaction Conditions	Operation in experiment
89.6%		Method A:; [00082] At 20-25 C., 24.6 mmol of ethyl bromopyruvate were added to 5.0 g (24.2 mmol) of thioamide in 47 ml of isopropanol, and the mixture was stirred for 5 h. 24.0 mmol of NaOH as a 20% strength aqueous solution of sodium hydroxide were then added, the product was extracted with methyl tert-butyl ether, the organic phase was washed with water and saturated sodium chloride solution and dried over sodium sulfate and the solvent was completely stripped off. This gave 6.2 g of the ethyl thiazole carboxylate, corresponding to a yield of 89.6%. [00083] 1H-NMR (DMSO-d6, in ppm): 8.41 (s, 1H, Ar-H), 7.86 (t, broad, NH), 4.41 (d, 2H, CH2), 4.30 (q, 2H, CH2), 1.40 (s, 9H, tert-butyl), 1.30 (t, 3H, CH3).
85%	With calcium carbonate; In ethanol; for 12h;	Compound 24 (10.53g, 55 . 4mmol) dissolved in anhydrous ethanol (100 ml), added calcium carbonate (11.08g, 111mmol), instillment bromo pyruvic acid ethyl ester (10.4 ml, 83mmol), reaction 12h through the diatomite filter, decompression turns on lathe ethanol, the residue is dissolved in ethyl acetate (300 ml) is dissolved, the organic phase is washed with saturated sodium bicarbonate solution, dried anhydrous sodium sulfate, after concentrating the residue by silica gel column chromatography, the obtained crude product with petroleum ether and ethyl acetate is recrystallized to get white solid compound 25 (13.47g, 85%).
81.7%		Method B:; [00085] At 20-25 C., 1.07 mol of ethyl bromopyruvate were added to 200 g (1.05 mol) of thioamide in 2.0 l of ethanol and 105 g of KHCO3 powder, and the mixture was stirred overnight. 225 ml of water and 50 g of 20% strength aqueous sodium hydroxide solution were then added, about 600 ml of ethanol were distilled off, 500 ml of water were added and the mixture was cooled to 0 C. The precipitated solid was filtered off and dried. This gave 246 g of ethyl thiazole carboxylate which, according to NMR, was pure. This corresponds to a yield of 81.7%.

67%		To compound 387 (6.00 g, 31.5 mmol) dissolved in CH2CI2 (150 mL) was added ethyl bromopyruvate (6.76 g, 4.4 mL, 34.7 mmol). Stirred at room temperature for 5 h then concentrated. Added 3 A sieves (6 g) and EtOH (150 mL) and refluxed for 16 h. Filtered and concentrated to give a dark foam. Dissolved foam in 1:1 CH2CI2:EtOH (100 mL) and added triethylamine (6.40 g, 8.8 mL, 63.1 mmol) and tBOC anhydride (7.60 g, 34.7 mmol). Stirred at room temperature for 5 h then concentrated. Added 0.25 N NaOH (100 mL), extracted with CH2CI2, dried combined organic extracts (MgS04), filtered, and concentrated. Purified by silica gel chromatography (eluant: 10% EtOAc- CH2Cl2 to 30% EtOAc-CH2Cl2) to give 6.00 g (67%) of the product 388 as a brown oil. MS m/e: 287 (M+H). For n=2: MS m/e: 301 (M+H)
65%	With pyridine; In ethanol; for 24h;Inert atmosphere; Reflux;	Ethyl bromopyruvate (1.75 mL, 14.0 mmol) and pyridine (1.69 mL, 21.0 mmol) were added to a solution of 8 (1.33 g, 7.0 mmol) in dry EtOH (60 mL) under N2 atmosphere. The reaction mixture was refluxed 24 hs. The volatile components were removed in vacuo. The resulting residue was dissolved in EtOAc (40 mL), washed with water (30 mL) and brine (30 mL). The organic layer was dried with MgSO4, filtered and concentrated in vacuo. Purification by column chromatography afforded 5 (1.31g, 65%) as a brown solid. Rf = 0.5 (hexane/ EtOAc, 1:1); 1H NMR (400MHz, CDCl3) delta 1.39 (t, 3H, J = 7,1 Hz), 1.46 (s, 9H), 4.14 (q, 2H, J = 7.1 Hz), 4.64 (d, 2H, J = 6.3 Hz), 5.31 (bs, 1H), 8.11 (s, 1H5). 13C NMR (100MHz, CDCl3) delta 14.3, 28.3 (3C), 42.4, 61.5, 80.5, 127.9, 146.9, 155.6, 161.3, 170.0.
	In ethanol; at 20 - 25℃; for 5h;Product distribution / selectivity;	a) Boc-2-Aminomethylthiazole-4-carboxamide [00073] At 10 C., ethyl bromopyruvate (386 g, 1.98 mol) was added dropwise to a solution of Boc-glycinethioamide (370 g, 1.94 mol) in 3.9 liters of ethanol, and the mixture was then stirred at 20-25 C. for 5 h, after which 299 ml of a 25% strength aqueous ammonia solution were added. [00074] From 940 ml of this mixture (corresponds to 19.9% of the total volume), 380 ml of ethanol were distilled off, a further 908 ml of a 25% strength aqueous ammonia solution were added and the mixture was stirred at 20-25 C. for 110 h. The mixture was cooled to 0 C. and the solid was filtered off, washed twice with water and dried. This gave 60.1 g of the BOC-protected thiazole carboxamide of an HPLC purity of 97.9 area %, which corresponded to a yield over these two steps of 60.5%. [00075] 1H-NMR (DMSO-d6, in ppm): 8.16 (s, 1H, Ar-H), 7.86 (t, broad, 1H, NH), 7.71 and 7.59 (2×s, broad, 1H each, NH2), 4.42 (d, 2H, CH2), 1.41 (s, 9H, tert-butyl).

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[ 165667-54-9 ]

References: [1]ACS Medicinal Chemistry Letters,2013,vol. 4,p. 132 - 136.
[2]Journal of the American Chemical Society,2002,vol. 124,p. 11272 - 11273.

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[ 85363-04-8 ]
[ 96929-05-4 ]

References: [1]Bioorganic and Medicinal Chemistry,2003,vol. 11,p. 3475 - 3485.
[2]Tetrahedron,1988,vol. 44,p. 5833 - 5844.

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